In-line monitoring of the freeze-drying process by means of heat flux sensors

The final qualities of a pharmaceutical product can be adversely affected by a suboptimized freeze-drying process. Multiple variables and operating conditions come into play, thus making the overall process difficult to control. In this study, we show how heat flux sensors can guide the in-line monitoring of freezing and primary drying of placebo formulations, leading to significant insights that contribute to our understanding of the phenomena involved. It was found that heat flux sensors can be used as a practical and robust tool to monitor a lyophilization cycle by defining the processing time and investigating different process scenarios. Concerning the freezing step, the heat flux sensors proved to be an effective way to detect both nucleation and end of crystal growth. Additionally, the sensors' signal highlighted the end of cooling and freezing steps and thus helped to eliminate uncertainty about the time required to reach thermal equilibrium across the batch. An ultimate potential of the devices was addressed to build the design space for freezing and primary drying, laying the foundations for new research on this topic.